2-amino-5-alkenyl-1, 3, 4 thiadiazoles and process for making the same



Patented May 13,1947

2 AMlINO-5-ALKENYL 1,3,4 THIADIAZOLES AND PROCESS FOR MAKING THE SAME Lucas P. Kyrides and Ferdinand B. Zienty, St. Louis, and Robert W. Stephenson, Webster Groves, Mo., assignors to Monsanto Chemical Company, St. Louis, Mo., a corporation of Delaware No Drawing. Application March 12, 1945,

' Serial No. 582,411

7 Claims. (01. 260-302) This invention relates to substituted thiadiazoles and more particularly to certain 2-amino- 5-alkenyl thiadiazol'es.

The compounds of the present invention have the following structural formula Alkenylin which the alkenyl residue has from 2 to 4 carbon atoms in its structure. The 2-amino-5- all-renyl-1,3,4-thiadiazoles embraced within the scope of the present invention may be found useful for their properties as analgesics and are also useful in the preparation of other types of therapeutic or pharmaceutical agents. The acetal sulfanilyl and the sulfanilyl derivatives of the 2-amino-5-alkenyl-1,3,4-thiadiazoles of the present invention possess marked activity in the control of bacterial growth. The salts of the respective compounds employed within the scope of the present invention are also contemplated as being within the scope of this invention.

The following 5-alkenyl derivatives of z-amino- 1,3,4-thiadiazole are illustrative of the novel compounds of the present invention: vinyl, allyl, propenyl, isopropenyl, 1,2-butenyl, 2,3-butenyl, 3,4- butenyl, isobutenyl, secondary butenyl and tertiary butenyl.

The 2-amino-5-alkenyl-1,3,4-thiadiazoles of the present invention may be prepared by any desired procedure. One procedure found useful is that which involves condensation of the appropriate alkenoyl chloride with thiosemicarbazide, the solution of the resulting reaction product in water and the subsequent recovery of the product from alkaline solution. An alternative procedure is that which involves the condensation of the appropriate chloralkanoyl chloride 'with thiosemicarbazide, the splitting ofl of HCl by means of hydrolyzing agents, such as caustic soda, from the resulting reaction product and the subsequent recovery of the desired product from alkaline solution. The acetyl sulfanilyl derivatives of the substituted thiadiazoles of the present invention may be prepared by reacting N-acetylsulfanilyl chloride with the appropriate 2-amino-5-alkenyl- 1,3,4-thiadiazole. Other acyl residues may be present on the sulianilyl residue in place of the acetyl residue, for example, formyl. propionyl or butyryl residues. The sulfanilyl derivative may be prepared therefrom by hydrolysis of the appropriate acyl derivative in alkaline solution. The sulfanilyl derivative may be prepared also by reduction of the 2-(p-nitrobenzenesulfonyl)-5- alkeny1-1,3,4-thiadiazoles. The latter compounds may be prepared by reaction of p-nitrobenzenesulfonyl chloride with the appropriate Z-amino- 5-alkenyl-1,3,4-thiadiazole.

The following examples will serve to illustrate suitable procedures for preparing the novel compounds oi the present invention. These examples are not to be construed as limiting the scope of the invention.

EXAMPLE I 2-amino-S-propenyl-LbA-thiadiazole Thirty-seven grams (0.354 mole) of crotonyl chloride was cooled by means of an ice bath'and 32.2 grams (0.354 mole) of thiosemicarbazide was added. The mixture was agitated for 8 hours and cooled during that period by means ofan ice bath. Thereafter the ice bath was-replaced by a water bath and the agitation was continued. After nine hours of agitation the mixture became solid. The solid material was dissolved in 200 cc. of water and the solution was filtered. The filtrate was rendered alkaline with 20% caustic soda solution and the solid product was filtered off, washed and dried. Melting point 170-175" C. Weight, 11.3 grams (22.6%).

EXAMPLE It 2- (N -acetylsuljanflamido) 5-propenyl-1 ,3,4

thiadiazole EXAMPLE IJI Z-sulfanilamido 5-propenyl-1,3,4-thiadiazole A solution of 17.5 grams (0.051s mole) of 2- (N4- acetylsulfanilamido 5 propenyl 1,3,4 thiadiazole in cc. of water containing 5.2 grams of sodium hydroxide was refluxed for 3 hours. Thereafter the solution was cooled and rendered acidic with glacial acetic acid. The product which separated was .filtered ofi, washed with water and dried. Weight 4.5 grams (29%). Melting point 177-178" C. (Decompn).

The mixture was stirred at room tem- 3 ExmuIV Z-amlno-S- (1 '-isobuten1ll) -1,3,4-thiadiazole the mixture was thereupon permitted to come to room temperature (approx. C.). The-mixture was allowed to stand for 9 hours and was thereafter dissolved in 200 cc. of water. The resulting solution was filtered. A sufiicient quantity of 20% caustic soda solution was added with cooling until the solution was rendered alkaline.v

4 ghalilyl-lsA-thiadiazole, was filtered of! and e s In place of gamma-chlorobutyryl chloride, 71 grams (0.5 mole) beta-chlorobutyryl chloride may be employed. Likewise, in place of gamma chlorobutyryl chloride, 52 grams (0.05 mole) of vinyl acetyl chloride may be employed.

Exsxru: VHI 2- (N-acet1!lsul/ nilamido) -5-a1lyl-1,3,4.. thiadtczole A solution of 14 grams (0.1 mole) of 2-amino- 5-allyl-1,3,4-thiadiazole in 130 cc. of dry pyridine was prepared. To this solution wasadded slowly with agitation, 18.2 grams ofN-acetylsulfanilyi chloride. The mixture waastirred at room tem- The product which separated out was filtered off and washed with water, and dried at 80-00 C. Weight, 12.6 grams (40.7%). Melting point 193- 197C.

Exurru V z-(N -acetylsuljanilamidol-5 (1'-isobutearl)- 1,3,4-thiadidzole A solution of 15.5 grams (0.1 mole) of 2-amino- 5-(1'-isobutenyl -1,3,4-thiadiazole in 140 cc, of dry pyridine was prepared. Thetemperature of the solution was regulated to a point below C. To the solution was added slowly with agitation 27 grams of N-acetylsulfanilyl chloride. The mixture was agitated overnight and thereafter was heated at 50-80' C. for one hour. Thereupon. 140 cc. of water was added and 160 cc. of theresulting mixture was distilled off. The desired product crystallized out in the still residue upon cooling and was thereafter filtered off and dried at 80-90" C. Weight, 30.6 grams (87.4%). Melting point 240 C.

Exnlrts VI Z-suljaniiamido-S-(I'-isolrutcnul) -1.:, thiadiazole Five grams (0.0142 mole) of 2-(N -acetylsulfanilsmido) -5-(1'-isobutenyl) 1,3,4 thiadiazole was dissolved in a solution of 1.5 grams of sodium hydroxide in 37.5 cc. of water at the boiling point 7 or the solution'and the resultingmixture was refluxed for 3 hours. The mixture was thereupon cooled and acidified with glacial acetic acid. The product was filtered ofi and dried at Til-80 C.

overnight. Weight, 4.2 grams. Melting point I approx. 235 C.

Seventy-one grams (0.5 mole) of gammachloro-butyryl chloride was cooled by means of an ice bath and 39 grams (0.5 mole) of thiosemicarbazide was added. The mixture was agitated for 8 hours and cooled during that period by means of an ice bath. Thereafter the ice bath was replaced by a water bath and the a tation was continued. When the mixture became solid,- the solid material was dissolved in 200 cc. of water and the solution was filtered. The filtrate was rendered alkaline with 20% caustic soda solution and the solid product was filtered off. The wet cake, 2-amino-5-(3'-chloropropyl)- 1,3,4-thiadiazole, was placed in 400 cc. of alcohol containing 50 grams of sodium hydroxide. Thereafter the mixture was refluxed for 3 hours, diluted with water and the alcohol was distilled oif. After coolins, the solid product, 2-aminoperature overnight and subsequently was heated to 60 C. for one hour. Thereafter cc. of

water was added and the product which precipi-.

tated was filtered off, washed with water and Z-suljantlamido-S-allwl-IJA-thiadialole A solution of 13.3 grams (0.05 mole) of a- I Exams: X Z-amino-5-vinul-1,3,4-thiadiazole A mixture of 58 grams (0.5 mole) of betachloropropionyl chloride and 39 grams (0.5 mole) of thiosemicarbazide was prepared and agitated for 2 hours at a temperature below 10 C. Thereafter the temperature of the mixture was allowed to rise to room temperature (approx. 25 0.).

After several hours of agitation, the reaction mixture was dissolved in approx. 400 cc. of warm 50% alcohol containing 50 grams of sodium hy-- droxide. Thereafter the mixture was refluxed for 3 hours, water was added, the alcohol was distilled off, and the mixture was cooled. The solid product, 2-amino-5-vinyl-l,3,4-thiadiazole,

was filtered off, washed and dried. In place of v I beta-chloropropionyl chloride, alpha-chloropropionyl chloride may be employed.

ExmLIXI Z-(IW-acetylsulfanilamido) -5-vinvl-1,8,lthiadiazole A solution of 12.7 grams (0.1 mole) of z-amino- 5-vinyl-1,3,4-thiadiazole in 150 cc. of dry pyridine was prepared. The temperature of the solution was regulated to a point below 30 C. To the solution was added slowly with agitation 78.2 grams of N-acetylsulfanilyl chloride. The mixture was agitated overnight and thereafter was heated at 50-60 C. for one hour. Thereupon cc. of water was added and cc. of the resulting mixture was distilled oil. The desired product crystallized out in the still residue upoz'i cooling and was thereafter filtered off and dried.

Exams: XII

2-sullanilamidO-5-vinyl-1,3,4-thiadiazole Ninety-nine grams (0.05 mole) of 2-(N -acetylsulfanilamido)-5-vinyl-l,3,4-thiadiazole was dissolved in a solution of 3 grams sodium hydroxide in 80 cc. of water at the boiling point of the so- I 50' grams of sodium lution and the resulting mixture was refluxed for 3 hours. The mixture was thereupon cooled and acidified with glacial acetic acid. The product was filtered off. washed with water and dried at 70-80 C. overnight.

Exam XIII Z-amino-S-isoiropenyl-I,3,4-thiadiazole filtered oflf, washed and dried.

As an alternative procedure, a mixture of '71 grams (0.5 mole) of beta-chloroisobutyryl chloride and 39 grams (0.5 mole) of thiosemicarbazide was prepared and agitated for 2 hours at a temperature below C. Thereafter the temperature was allowed to rise to room temperature (approx. 25 C.). After several hours of agitation, the reaction mixture was dissolved in approx. 400 cc. of warm 50% alcohol containing hydroxide. Thereafter the mixture was refluxed for 3 hours, water was added, the alcohol distilledoif and the mixture was cooled. The solid product was filtered oil. washed and dried. v

Exams: XIV

Z- (N-acetzllsulfanilamido) -5-isopropenyl- 1,3,4-thiadiazole This compound was prepared according to the procedure described in Example 2,

substituting 11 grams or Z-amino-5-isopropenyl-1,3,4-thiaj diazole for the 2-amino-5-propenyl-1,3,4-thiadiazole employed in that procedure.

. Exmn XV 2-sulfanilamido-5-is0propenwl-1,3,4-thiadtazole acid in aqueous or organic solvent solution. according to the procedure known in this art for the preparation of acid salt derivatives of basic organic nitrogen compounds. I

While the compositions of the present invention have been described and illustrated in the foregoing specification and examples, it is to be observed that the present invention is not to be construed as being limited in respect to any particular substances, proportions, conditions or combinations except as defined in the claims.

We claim:

1. 2-amino-5-alkenyl-1,3,4-thiadiazoles of the formula type in which the alkenyi residuehas from 2 to 4 carbon atoms and salts thereof, prepared for use as therapeutic agents and as intermediates. for

therapeutic agents. 7 g

2. 2-amino-5-vinyl-1,3,4-thiadiazole, prepared for use as a therapeutic agent and as an intermediate for therapeutic agents.

3.\ 2-amino-5-propenyl-1.3,4-thiadiazole, prepared for use as a therapeutic agent and as an intermediate for therapeutic agents.

4. 2-amino- 5 isopropenyl 1,3,4 thiadiazole, prepared for use as a therapeutic agent and as an intermediate for therapeutic agents.

5. A process for preparing 2-amino-5-alkenyl- 1,3.4-thiadiazoles comprising condensing an allrenoyl chloride having in the alkenyl radical bazide. i

6. A process for preparing 2-amino-5-alkenyle 1,3,4-thiadiazoles, comprisinz condensing a chicroalkenoyl chloride having from 3 to 4 carbon atoms inthe allryl radical thereof with thiosemicarbazide, and reacting the resulting 2-amino-5- ch1oralkyl-1,3,4-thiadiazole with a hydrolyxing thereof with thiosemicaragent until HCl has been removed from the com- I fined in claim 1.

' LUCAS P. KYRHDEB.

FERDINAND B. ZIENTY.

ROBERT STEPHENSON. v

REFERENCES CITED The following references are of record in file of this patent: I g

u'm'ran s'ra'rss PATENTS mt... Name i Date 2,358,031. Roblin, Jr. et a1. Bept. 12, 1944 ,331,749. Watt Oct. 12, 1943.

Chemical Abstract. vol. 56, 70094,'1943.-

from 2 to 4 carbon atomsd. Acid salt derivatives of the compounds de- 

